Current Indications, Cost, and Clinical Use of Anti-PCSK9 Monoclonal Antibodies


It has been a decade since the initial reported association between loss of function genetic variants impairing the gene encoding anti-proprotein convertase subtilisin/kexin type 9 (PCSK9), a lifelong reduction in LDL cholesterol (LDL-C) levels, and protection from cardiovascular disease.1 In this short span of time, anti-PCSK9 monoclonal antibodies were developed and recently shown to have favorable safety and efficacy profiles in phase III lipid-lowering trials. These antibodies target PCSK9, a protease that binds and promotes degradation of the LDL receptor, leading more LDL receptors on the surface of hepatocytes, and a lower level of serum LDL-C.

A synergistic benefit of using PCSK9 inhibitors with statins is also proposed since statin therapy causes upregulation of PCSK9 levels in hepatocytes. PCSK9 inhibitors demonstrated an unprecedented 60% reduction in LDL-C on the background of statin therapy with evolocumab in the OSLER (Open Label Study of Long Term Evaluation Against LDL-C) clinical trials and with alirocumab in the ODYSSEY LONG TERM (Long-term Safety and Tolerability of Alirocumab [SAR236553/REGN727] Versus Placebo on Top of Lipid-Modifying Therapy in High Cardiovascular Risk Patients With Hypercholesterolemia) clinical trial.2,3 Furthermore, addition of PCSK9 inhibitors reduced cardiovascular events by approximately 50%, although these phase III lipid-lowering trials were not designed as outcome trials, and the event rates were low.

Current Indications

In light of the promising findings from the phase II and III lipid-lowering trials, during the summer of 2015 the US Food and Drug Administration fast-track approved the use of anti-PCSK9 monoclonal antibodies, namely evolocumab and alirocumab, as adjuncts to diet and maximally tolerated statin therapy for patients with familial hypercholesterolemia (FH), and those with clinical atherosclerotic cardiovascular disease (ASCVD), requiring a greater reduction in LDL-C levels. These indications were selected since these subgroups confer the highest risk of future cardiovascular events, and were previously studied in phase II and III lipid-lowering trials. Although several trials studied the use of PCSK9 inhibitors in other patient subgroups, such as statin-intolerant patients in the GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) trial, these agents are not currently approved for other indications.4 Nevertheless, a meta-analysis by Navarese and colleagues incorporating 24 phase II and III trials revealed no heterogeneity among the included trial results, proposing that the benefits of PCSK9 inhibitors can be extended to other subgroups of patients studied.5 Table 1 shows indications for evolocumab and alirocumab from their US prescribing labels.

Table 1: FDA Approved Indications for Anti-PCSK9 Monoclonal Antibodies in Addition to Diet and Maximally Tolerated Statin Therapy for Additional LDL-C Lowering


Clinical ASCVD*

Heterozygous FH

Homozygous FH

Evolocumab (Repatha)




Alirocumab (Praluent)




*Clinical ASCVD includes acute coronary syndromes, history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin.


Alirocumab and evolocumab are estimated to cost approximately $14,350 per patient for a one-year supply in the United States, or approximately $1200 per month.6 The cost of these monoclonal antibodies is comparable to other biologic agents currently in use. For example, the average cost for etanercept and adalimumab, tumor necrosis factor blocking agents used for rheumatoid arthritis, ranges from approximately $1,000 to $2,500 per month, respectively. A report by the Institute for Clinical and Economic Review (ICER) showed that PCSK9 inhibitors produced ICER values of $290,000, $302,000, and $170,000 per quality-adjusted life-year (QALY) free of major adverse cardiac event in patients with FH, in secondary-prevention patients with LDL-C ≥70mg/dL on statin therapy, and in patients following a first myocardial infarction (MI), respectively. Thus, it is estimated based on these calculations that the cost of these drugs would need to be reduced substantially to reach a willingness-to-pay threshold of $50,000 per QALY gained. Using a more generous willingness-to-pay threshold of $150,000 per QALY gained, these agents would be cost-effective at half the current price for the first two scenarios, and with a price reduction of approximately 12% in patients with first MI. However, it is important to note that this ICER analysis based cardiovascular event rate assumptions on the meta-analysis by Navarese and colleagues from studies with very low event rates.5 Therefore, the cost-effectiveness should be more favorable in higher risk patients currently being studied in the ongoing phase III outcomes studies.7-10

The cost-effectiveness of these agents may be even more favorable if PCSK9 inhibitors cause plaque regression, similar to statins, resulting in a "legacy effect" after discontinuation. Plaque regression and stabilization is another benefit of lipid-lowering therapy (particularly of statins), follows a linear relation to the achieved LDL-C, and is thought to play a significant role in persistent relative cardiovascular event reduction in post-trial follow-up.11 Such a legacy effect was reported in the WOSCOPS (West of Scotland Coronary Prevention Study) trial in which patients receiving 5 years of statin therapy continued to have significantly reduced mortality even 15 years after the trial was completed.12 PCSK9 inhibitors, offering a more robust and persistent LDL-C lowering, could provide a more profound legacy effect, such that uninterrupted life-long therapy with PCSK9 inhibitors may not be required. Thus, it is interesting to speculate whether patients could be treated for several years with a PCSK9 inhibitor and then have an interval break to reduce drug cost. Such a strategy should be prospectively tested in a follow-up study if the ongoing phase III outcome studies are positive.

Clinical Use

There are a four ongoing and highly anticipated phase III cardiovascular outcome trials of PCSK9 inhibitors. Table 2 summarizes the main characteristics of these trials including the populations studied. The populations studied in these phase III outcome trials will establish the future indications for PCSK9 inhibitors. For example, positive results in these trials could extend the indications of these agents to patients with high risk of cardiovascular events with LDL-C levels ≥70 mg/dL.

Table 2: Phase III Cardiovascular Outcome Trials of PCSK9 inhibitors










ODYSSEY Outcomes




Sample size






4-52 wks post-ACS

MI, stroke or PAD

High risk of CV event


Evidence-based med Rx

Atorvastatin ≥20 mg or equivalent

Lipid-lowering therapy

LDL-C (mg/dL)

≥ 70

≥ 70


≥ 100

PCSK9 inhibitor dosing


Q2W or Q4W



CHD death, MI, ischemic stroke, or hospitalization for UA

CV death, MI, stroke, hospitalization for UA, or revascularization

CV death, MI, stroke, or urgent revascularization



Before end of 2016


Although outcome trial data are pending, we can project potential cardiovascular outcome results with PCSK9 inhibitors based on the statin trials. The landmark Cholesterol Treatment Trialists' (CTT) meta-analysis projected a 21% reduction in major vascular events per 1 mmol/L reduction in LDL-C with statins over a median of approximately 5 years of follow up.13 In the aforementioned trials,2,3 PCSK9 inhibitors achieved an LDL-C reduction of 1.83 mmol/L and 1.89 mmol/L for alirocumab and evolocumab, respectively. When the CTT meta-analysis projections are applied to the LDL-C level reductions observed with PCSK9 inhibitors (assuming a 10% early stoppage rate), we estimate approximately35% reduction in major vascular events, ~42% reduction in major coronary events, ~25% reduction in stroke and ~15% reduction in all-cause mortality.

These estimations are based on cardiovascular event reductions observed from trials with statin therapy, and statins also have been associated with several pleiotropic benefits beyond LDL-C reduction that may contribute to a reduction in cardiovascular events.14 If pleotropic effects are important, then we may see a lesser clinical benefit of PCSK9 inhibitors than predicted on LDL-C reduction alone. On the other hand, recently, the non-statin ezetimibe reduced LDL-C and cardiovascular events to the degree predicted by the CTT meta-analysis based on LDL-C reduction alone in the IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]) trial.15 The same pleotropic effects reported with statins are not believed to be present with ezetimibe to the same degree; thus the data from IMPROVE-IT support the hypothesis that it is the LDL-C lowering effect alone that is the key to the reduction in cardiovascular events.

The safety profile of anti-PCSK9 monoclonal antibodies are also important to consider. Side effects thus far have been attributed to injection site reactions including erythema, pruritis, swelling and tenderness. The most common non-injection side effect reported has been nasopharyngitis. The ongoing studies are evaluating neurocognitive function in patients since there was a numeric imbalance in neurocognitive adverse events in individuals receiving PCSK9 inhibitors in OSLER and ODYSSEY LONG-TERM trials.16 While these events, including confusion and memory impairment, are uncommon and have not be consistently associated with on-treatment LDL-C levels,16 given the very low LDL-C that will be achieved with PSCK9 inhibitors (most patients will achieve <50 mg/dl, and a substantial proportion will achieve <25 mg/dL) this deserves careful evaluation. Of note, long term exposure (average 6 years) to ezetimibe plus simvastatin in a cohort of 970 patients in the IMPROVE-IT trial that achieved an LDL-C below 30 mg/dL at 1 month was not associated with an increase in adverse events.17

Findings from the ongoing PCSK9 inhibitor outcome trials undoubtedly will result in changes to existing guidelines on cholesterol treatment. The most recent 2013 ACC/AHA cholesterol guidelines de-emphasized LDL-C targets, recommended statins as the primary evidence-based agent to reduce cardiovascular events, and thereby the use of non-statin lipid lowering agents were discouraged. Following the publication of the positive results of the IMPROVE-IT trial, as well as encouraging data with PCSK9 inhibitors in the phase III lipid-lowering trials, the 2016 ACC expert consensus document expanded the role of non-statin therapies for LDL-C lowering in the management of ASCVD.18 In this expert consensus document, addition of non-statin therapies, namely ezetimibe as the first line and PCSK9 inhibitors as the second line of choice, is encouraged for patients at high ASCVD risk who continue to have high LDL-C despite maximally tolerated statin therapy. New more comprehensive Cholesterol Treatment guidelines are expected after completion of the phase III cardiovascular outcome trials with PCSK9 inhibitors.


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Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Prevention, Vascular Medicine, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Diet

Keywords: Acute Coronary Syndrome, Angina, Unstable, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Arthritis, Rheumatoid, Biological Factors, Cholesterol, LDL, Confusion, Diet, Drug Costs, Erythema, Hepatocytes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Ischemic Attack, Transient, Myocardial Infarction, Nasopharyngitis, Peptide Hydrolases, Peripheral Arterial Disease, Pharmaceutical Preparations, Proprotein Convertases, Pruritus, Quality-Adjusted Life Years, Receptors, LDL, Risk Factors, Stroke, Simvastatin, Subtilisins, Tumor Necrosis Factors, Up-Regulation, United States Food and Drug Administration

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